Zhao Yang, Yao Bu-Fan, Kou Chen, Xu Hai-Yan, Tang Bo-Hao, Wu Yue-E, Hao Guo-Xiang, Zhang Xin-Ping, Zhao Wei
School of Medicine and Health Management, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.
Front Pharmacol. 2020 Feb 4;11:14. doi: 10.3389/fphar.2020.00014. eCollection 2020.
Cefepime is used to treat severe infections in neonates. Pharmacokinetic data have only been evaluated among preterm neonates and population pharmacokinetic model lacked external validation. Hence, our aim is to obtain the population pharmacokinetic parameters of cefepime with large sampling and optimize the cefepime dosage regimen for neonatal infection based on developmental pharmacokinetics-pharmacodynamics.
Blood samples from neonates and young infants treated with cefepime were collected using the opportunistic sampling design. The concentration of cefepime was determined using high performance liquid chromatography with ultraviolet detection. The population pharmacokinetic model was established using NONMEM software.
One hundred blood samples from eighty-five neonates were analyzed. The population pharmacokinetics of cefepime were described by a one-compartment model with first-order elimination. Covariate analysis indicated that serum creatinine concentration, postmenstrual age and current weight had significant impact on the pharmacokinetic parameters of cefepime. Monte Carlo simulation results showed that the current dosage regimen (30 mg/kg, q12 h) had a high risk of insufficient dose. For 70% of neonates to obtain a higher free drug concentration than the minimum inhibitory concentration during 70% of the dosing interval, 50 mg/kg q12 h was needed with a susceptibility breakpoint of 4 mg/l. For a minimum inhibitory concentration of 8 mg/l, 40 mg/kg q8 h was recommended for all neonates.
A population pharmacokinetic model of cefepime in neonates and young infants was established. According to simulation results based on the developmental pharmacokinetics-pharmacodynamics, different dosage regimens should be given depending on pathogens and the postmenstrual age.
头孢吡肟用于治疗新生儿严重感染。其药代动力学数据仅在早产儿中进行过评估，且群体药代动力学模型缺乏外部验证。因此，我们的目的是通过大量采样获得头孢吡肟的群体药代动力学参数，并基于发育药代动力学 - 药效学优化新生儿感染的头孢吡肟给药方案。
采用机会性抽样设计收集接受头孢吡肟治疗的新生儿和幼儿的血样。使用带紫外检测的高效液相色谱法测定头孢吡肟浓度。使用NONMEM软件建立群体药代动力学模型。
分析了来自85名新生儿的100份血样。头孢吡肟的群体药代动力学由具有一级消除的单室模型描述。协变量分析表明，血清肌酐浓度、孕龄和当前体重对头孢吡肟的药代动力学参数有显著影响。蒙特卡洛模拟结果表明，当前给药方案（30mg/kg，q12h）存在剂量不足的高风险。对于70%的新生儿，要在70%的给药间隔期间获得高于最低抑菌浓度的游离药物浓度，当敏感折点为4mg/l时，需要50mg/kg q12h。对于最低抑菌浓度为8mg/l，建议所有新生儿采用40mg/kg q8h。
建立了新生儿和幼儿头孢吡肟的群体药代动力学模型。根据基于发育药代动力学 - 药效学的模拟结果，应根据病原体和孕龄给予不同的给药方案。
